The goal of this proposal is to obtain funding for a 15 Tesla Bruker SolariX hybrid FTICR mass spectrometer to be housed in the UW-Madison Pharmacy MS Facility. This new instrument will offer several unique features: (1) Ultra-high resolution and high mass accuracy MS, MS/MS, and MSn capabilities;(2) Multiple ionization sources;(3) Enhanced de novo sequencing of peptides with multiple fragmentation techniques;(4) High resolution tissue imaging;(5) Quantitation based on isotopic labeling strategies;and (6) Ability to analyze small molecules as well as full-length proteins. This new instrument will provide advanced MS capabilities to support the research of 28 highly productive NIH-funded investigators with 49 ongoing projects. The use of high resolution MS and tandem MS will help to address multiple levels of human health-related research including, (a) understanding of fundamental biological and disease related processes (neuropeptides involved in feeding stimuli, Dr. Li;neuropeptides and proteins involved in signaling in a nematode model, Dr. Stretton;plasma membrane proteins responsible for maintenance of the blood-brain barrier, Dr. Shusta;proteomic changes in monocytes in response to biomaterials, Dr. Kao;environmental toxicological responses Drs. Elfarra, and Heideman;protein signaling complexes in asthma, Dr. Malter;protein-protein interactions in the visual system Dr. Ruoho;protein folding and biosynthesis, Dr. Cavagnero;prostate development, stem cell maintenance and tumor growth, Drs. Peterson, Bushman and Marker;signaling events in limb development, Dr. Sun;lipids and their role in sleep regulation, Dr. Yin), (b) discovery of biomarkers (for neurodegenerative diseases, Drs. Messing and Li;differences in the brain proteome in mouse models of mental retardation, Dr. Malter;changes in astrocyte secretome associated with neuronal protection, Dr. Johnson), (c) posttranslational modification mapping of proteins in disease process (modifications involved in Alzheimer's disease, Drs. Murphy and Wang;breast cancer, Dr. Xu;leukemia, Dr. Collier), (d) discovery/development of novel natural product pharmaceuticals (validate intermediates and products in the total synthesis of natural products, Dr. Hsung;identify novel polyketides and investigate enzymatic mechanisms of polyketide synthesis, Dr. Shen;structural characterization of glycorandomized pharmaceuticals, Dr. Thorson;structural elucidation of new natural products, Dr. Bugni), (e) improvement of drug delivery (characterization of novel biopolymers for drug delivery, Dr. Kwon;characterization of new fluorine-containing compounds for delivery of anesthetics, Dr. Mecozzi), and (f) clinical pharmaceutical analysis (evaluation of pharmacological profiles of anesthetics, Dr. Pearce;investigation of drug metabolism in clinical samples, Drs. Kolesar, Bailey, and Wilding). Progress on this broad array of projects will be catalyzed by the effective usage of the new instrument through close cooperation among the user groups, Dr. Li, a highly productive faculty member with more than 17 years of experience in biological mass spectrometry, and Dr. Scarlett, the UW-Madison Pharmacy-MS Facility Director. PUBLIC HEALTH RELEVANCE: Successful acquisition of a high resolution Bruker SolariX Hybrid FTICR mass spectrometer will have significant and broad impact on a wide array of biomedical research projects conducted on the health sciences campus at the University of Wisconsin-Madison (UWM). This cutting-edge instrument will provide advanced mass spectrometric capabilities that facilitate deciphering molecular details involved in a broad spectrum of biological processes as well as disease progression, diagnosis and treatment. This instrumentation enhancement will support 30 major and minor users with 49 funded federal grants or contracts, and will accelerate the pace of ongoing research in 13 departments or divisions within five colleges or schools and two centers at UWM as well as being available to the broader scientific community in Madison and the State of Wisconsin.